This application is the national phase under 35 U.S.C. xc2xa7371 of PCT International Application No. PCT/KR99/00264 which has an International filing date of May 28, 1999, which designated the United States of America and was published in English.
The present invention relates to novel cathecol hydrazone derivatives which inhibit the enzymatic activity of phosphodiesterase IV or tumor necrosis factor. These compounds may be useful in prevention or treatment of bronchial asthma, arthritis, bronchitis, chronic atretic airway, psoriasis, allergic rhinitis, dermatitis, AIDS, Crohn""s disease, septicemia, septic shock, other inflammatory diseases such as cachexia, TNF related diseases, etc. Also, the present invention relates to a method for producing said compounds and a pharmaceutical composition containing said compound.
Phosphodiesterase IV is an enzyme that specifically hydrolyzes cAMP (cyclic adenosine 3xe2x80x2,5xe2x80x2-monophosphate) into inactive adenosine 3xe2x80x2,5xe2x80x2-monophosphate. The cAMP has been shown to be a second messenger mediating the cellular responses to external stimuli and to act as relaxing or contradicting bronchial muscles.
The inhibition of phosphodiesterase IV leads to the prevention of broncospasm by maintaining the concentration of cAMP and also induces an anti-inflammation. Therefore, compounds that inhibit phosphodiesterase IV should be effective in treating asthma and the like diseases.
It is known that tumor necrosis factor (TNF) is implicated in infectious disease such as cachexia and autoimmune disease. Also, TNF appears to act as a primary mediator for inflammatory reaction such as septicemia and septic shock.
Therefore, it is expected that compounds with the inhibitory activity against phosphodiesterase IV or TNF will be pharmaceutically valuable and there is always a need to develop new compounds which inhibit phosphodiesterase IV and TNF.
Many compounds have been suggested as inhibitors of phosphodiesterase IV and TNF. For example, EP 470,805 of American Home Product describes oximcarbamate and oximcarbonate of formula: 
wherein R is C3-7 alkyl or C3-7 cycloalkyl, R1 is halogen or lower alkyl, and R2 is amino, lower alkylamino, arylamino, lower alkoxy or aryloxy.
U.S. Pat. No. 5,393,798 of SmithKline Beecham Corporation describes phenylalkyl oxamide compound of formula: 
wherein R1 is C4-6 cycloalkyl, X is YR2 halogen in which Y is oxgen or sulfur, or lower alkyl, R3 and R5 are independently OR7, R4 is hydrogen or C1-2 alkyl, R6 is OR7 or NR7OR7, and R7 is hydrogen or C1-3 alkyl.
The present invention provides novel cathecol hydrazone derivatives of formula I: 
or pharmaceutically acceptable salts thereof, wherein
R1 is C1-7 alkyl or C3-7 cycloalkyl;
R2 is hydrogen, hydroxy, C1-5 alkyl or xe2x80x94CH2CH2C(xe2x95x90O)NH2;
R3 and R4 are independently hydrogen, C1-7 alkyl, xe2x80x94C(xe2x95x90X)xe2x80x94R5, or 2-, 3- or 4-pyridyl, prymidyl or phenyl substituted with one or two selected from a group consisting of halogen, C1-6 alkoxy, nitro, trifluoromethyl, C1-6 alkyl and carboxyl, or R3 and R4 are directly bonded by C3-4 containing oxygen, sulfur or nitrogen to form a heterocyclic ring, X is oxygen, sulfur or NH, and R5 is C1-7 alkyl, xe2x80x94NHR6, CONH2 or 2-, 3- or 4-pyridyl, prymidyl or phenyl substituted with one selected from a group consisting of halogen, C1-6 alkoxy, nitrile, trifluoromethyl, C1-6 alkyl and carboxyl, and R6 is hydrogen, hydroxy, NH2, C1-5 alkoxy, C1-5 alkyl, pyridyl or phenyl.
The compound of formula I can be present as optical isomers or stereoisomers. Thus, the present invention includes such isomers and mixtures thereof.
The present invention provides a pharmaceutical composition for inhibiting phosphodiesterase IV or TNT which comprises a compound of formula I and a pharmaceutically acceptable carrier.
The compound of formula I can be prepared by the following reaction scheme I: 
wherein R1, R2, R3 and R4 are the same as defined above.
Some derivatives were synthesized by a known method (J. Med. Chem., 1994, 37, 1696). Hydrazine compounds were synthesized in yield of 60% to 90% in alcohol solvent using acid catalyst (Tetrahedron Lett. 1994, 35, 3711).